Handbookof

Olfactionand
Gustation
SecondEdition
Revisedand Expanded

editedby
RichardL. Doty
Uniaersityof Pennsylaania
.
Philadelfihia,Pennsylaania,
U. S.A.

Mancrr Drrxrn, INc. Nsw Yom. Bespr

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2B
Evaluation
of OlfactoryDeficitsby StructuralMedicallmaging
Cheng[i, RichardL. Doty, and David W. Kennedy
lJniversityof Pennsylvania,Philadelphia,Pennsylvania,U.S.A.
David M. Yousem
TheJohnsHopkins UniversitySchool of Medicine, Baltimore,Maryland, U.S.A.
I. INTRODUCTION
Olfactory dysfunction can generally be classified into (1)
conductive disorders caused by interference with the
accessof odorantsto the olfactory recepto(s,(2) peripheral
sensorineuraldisorders resulting from injury to the olfac-
tory receptors (within the olfactory mucosa), and (3) cen-
tral neural disordersof the olfactory bulb or tract or related
parts of the central nervous system such as the prefrontal
lobe, septal nuclei, amygdala, and temporal lobe. For
medical imaging and the anatomical approach,we catego-
rize olfactory dysfunction into two major groups: periph-
eral causes-sinonasal tract disorders-and central
causes- intracranial disorders. It is important to relate
olfactory deficits to the appropriate anatomical and patho-
logical changes. Unfortunately, clinical olfactory testing,
whether psychophysical or electrophysiological, is rarely
capable of localizing the source (aside from determining
whether it is on the right or left) or identifying the specific
causeof decreasedsmell function.
Modern medical imaging techniques offer a valuable
means for assessingthe basis of some disorders of olfac-
tion. Although revolutionary changesin medical imaging
techniques have occurred in the last few decades,only a
few articles have dealt with imaging studies related to
chemosensory disorders (Doty et al., 1999: Goodspeed
et al., 1987:'Kimmelman, 1991; Klingmuller et al., 1987;
Li et al., 1994; Schellinger et al., 1983; Yousem et al.,
593
1996, 1997, 1998, 1999). In this chapter we comprehen-
sively review the pertinent medical literature on this gen-
eral topic and detail our own experience.
II. IMAGING MODALITIES AND TECHNIQUES
Major advancesin pinpointing the anatomicaland patholog-
ical changesof many disordersof the sinonasalcavity and
brain have become possible as a result of the development
and refinement of imaging techniques(Carter and Runge,
1988;Healy, 1992;Jagustand Eberling, 1991;Jolleset al.,
1989; Reiman and Mintun, 1990; Shapiroand Som, 1989;
vogl, 1990; Yousem er al. 1996a,199',7b,1998). Even
though the imaging evaluationis not the diagnostic equiva-
lent to histological study, anatomical imaging, such as high-
resolution computed tomography (CT) and magnetic
resonance imaging (MRI), can not only map regional
lesions,but may also suggesta differential diagnosis(Carter
and Runge, 1988; Shapiroand Son, 1989; Som and Shapiro,
1988).On the other hand, functional imaging (PET, SPECT,
fMRI), which is reviewed in Chapter 12, affords one the
potential to explore regional pathophysiologicalchangesin
the living brain (Healy, 1992; Jagtst and Eberling, l99l;
Jolles et al., 1989; Reiman and Mintun, 1990;Yousemet al.,
I997b, 1999b, c). The relevant imaging modalities which
may be helpful in the evaluation of common causesof olfac-
tory deficits are reviewedin this section.
594
A. Plain Radiographs
Plain film radiography, i.e., the "sinus series," including
the Caldwell view, the Waters view, the lateral view, and
the base view, has long been a standard method of diag-
nosing nasal and paranasal sinus inflammatory disease.
Problems of overlap and nonspecific findings are impossi-
ble to avoid with plain films, and thus the study has been
largely replaced by CT. The most important deficit of the
plain film is its inability to provide the road map of the
ostiomeatal complex, which may guide endoscopic surgi-
cal intervention (Zinreich et a1., 1987). Plain radiographs
and conventional plain film tomography have virtually no
role in the imaging evaluation of olfactory dysfunction.
B. Computed Tomography
CT is well suited to the investigation of the sinonasalcav-
ities. BecauseCT scanningis as sensitiveto soft tissuedis-
easeas to bony changes,each scancan be photographedat
an appropriate window width and level to optimally see
insidious soft tissue differences in attenuation and fine
bony detail. To study soft tissue, the window widths range
from 150 to 400 Hounsheld units. Conversely, the bony
detail is best observed at wide window settings-from
2000 to 4000 Hounsfieldunits.The basicCT scanningpro-
tocol should include all of the nasal cavity, paranasal
sinuses, hard plate, anterior skull base, orbits, and
nasopharynx. The brain should be included if central
causesof olfactory dysfunction are suspected.The scans
are commonly performed in both the axial and coronal
planes for optimal assessmentof the complex paranasal
anatomy, but coronal scans are the most valuable for the
anterior naso-ethmoid (ostiomeatal) region. Alternatively,
thin sectionsin one plane with multiplanar reconstructions
may be adequate.For practical pu{poses,slice thicknesses
of 3-5 mm are often employed. For the evaluation of the
ostiomeatal complex (the maxillary sinus ostium,
infundibulum, uncinate process, and middle meatus),
3-mm-thick coronal sections are fairly standard unless
three-dimensional(3D) reconstructionsare requested.The
quality of the 3D images is improved by utilizing l-mm-
thick sectioning, which is rapidly performed with the new
spiral scanners(minutes) and multidetector scanners(sec-
onds). Intravenous contrast enhancement is usually
reserved for the identification of vascular lesions, tumors,
meningeal or parameningealprocesses,and abscesscav-
ities (Carter and Runge, 1988). Intrathecal contrastmay be
employed when cerebrospinal fluid leaks accompany the
olfactory deficits. High-resolution CT is the most useful
and cost-effective screening tool for the evaluation of
sinonasaltract infl ammatory disorders.
Li et al.
C. Magnetic Resonance Imaging
MRI's multiplanar capability is especially advantageousin
the evaluation of sinonasal tract neoplasmsand brain dis-
orders. MRI, however, is less sensitivefor the detection of
bony cortical abnormalities and landmarks. Soft tissue dis-
crimination, on the other hand, is more clearly illustrated
by MRI than by CT. Most soft tissue diseaseprocessescan
be accurately localized with a minor degree of tissue dif-
ferentiation, i.e., infection vs. tumor vs. hemorrhage.The
anatomical discrimination of the brain is much better using
MRI than CT. One can use thin sections, large matrices,
and smaller fields of view to improve resolution, yet main-
tain, high contrastto noiseusing T1-weightedscans(T1W)
or fast spin echo T2-weighted (T2W) images. T2-weighted
scanscan better delineatethe contrastbetween normal and
inflammatory or neoplastic tissue (Shapiro and Som,
1989). New phase sensitive inversion recovery pulse
sequencesor standardspoiled gradient echo sequencescan
highlight the gray-white matter differentiation and allow
better assessmentof the hippocampus, parahippocampus,
gyrus rectus, and entorhinal cortex regions. Segmentation
of images to separatecortical volume from whole brain
volume is customary for volumetric studies nowadays.
For the evaluation of skull base invasion by sinonasal
tumors, MRI is superior to CT (Paling et al., 1987).
Gadolinium enhanced scans are particularly useful at the
skull base to detect dural or leptomeningeal involvement.
Gadolinium-DTPA, a paramagnetic contrast agent, has
been widely utilized for distinguishing solidly enhancing
tumor from rim-enhancing inflammatory processes
(Brasch,1992;Yogl et al., 1990).
With regard to the olfactory system, CT and MRI play
complementary roles in evaluating sinonasal tract neo-
plasms (Shapiro and Som, 1989; Som et al., 1990).
However, MRI is the study of choice to directly visualize
the olfactory bulbs, olfactory tracts, and intracranial causes
of olfactory dysfunction (Klingmuller et aI., 1987; Suzuki
et a1.,1989;Yousemet al., 1993,1998, 1999a).
D. Nuclear Medicine
In general, conventional radionuclide imaging plays no
significant role in the diagnostic work-up of patients with
suspected sinonasal tract disease (peripheral causes of
olfactory deficits), except in the caseof cerebrospinalfluid
(CSF) leaks. Functional imaging studies, such as positron
emission tomography (PET) and single photon emission
computed tomography (SPECT), are valuable in detecting
alterations of regional brain function and biochemistry in
vivo (Alavi & Hirsch, 1991;Fowler et al., 1988;Jagustand
Eberling, 1991; Jolles et al., 1989, Reman and Mintun,
Medical Imaging of Olfactory Defrcits
1990). Recent studieshave suggestedthat functional imag-
ing is more sensitivethan anatomical imaging in detecting
abnormalities of the brain related to disorders such as
Alzheimer's disease and Parkinson's disease-conditions
associated with loss of olfactory function (Jagust and
Eberling,1991;Jolleset a1.,1989).
III. BASICANATOMYAND PHYSIOLOGY OF
THE OLFACTORY SYSTEM
Since the anatomy and physiology of the olfactory system
is discussedelsewherein this volume (seeChaptersl-9),
we only briefly mention this topic here. The sensationof
smell is induced by the stimulation of olfactory receptor
cells by volatile chemicals. The olfactory receptor cells,
i.e., the primary olfactory neurons,are encompassedin the
neuroepithelium, which is located at the top of the nasal
vault, the upper poftion of the nasal septum, the superior
surface of the superior nasal turbinate, sectorsof the mid-
dle turbinate, and the region of the cribriform plate.
Afferent information from the receptors is transmitted by
the olfactory nerves, which course through the cribriform
plate of the ethmoid bone to terminate in the glomeruli of
the olfactory bulb. In the olfactory bulb, the olfactory
neryes make synaptic contact with dendrites of mitral and
tufted cells. From there, the efferent neurons of the olfac-
tory bulb give rise to fibers forming the olfactory tracts,
which lie just under the gyrus rectus region in the olfactory
sulcus of the frontal lobes. Axons from mitral and tufted
cells project to central brain limbic system components
including the pyriform cortex and adjacent corticomedial
amygdala (which together form the uncus), the ventral
striatum, the parahippocampusarea,and the anterior olfac-
tory nuclei. From these areas there are widespread inter-
connections with many parts of the brain, including the
mediodorsal thalamus, hypothalamus, orbitofrontal and
dorsolateral frontal cortex, temporal cortex, and other
areasof the limbic system (seeChapters 8 and 9).
IV. PERIPHERAL CAUSES OFOLFACTORY
DISTURBANCE
Sinonasal tract disease is one of the common causes of
olfactory disturbance (Deems et al., I99l; Doty and
Mishra, 2001). The etiology of the olfactory deficits
among patients with nasal and paranasal sinus diseaseis
due, in many cases,to nasal airway obstruction. The influ-
ence of nasal obstruction on olfaction has been compre-
hensivelyreviewed (e.g., Doty and Frye, l9B9; Doty and
Mirshra, 2001) (see also Chapter 2l). Any cause of bilat-
eral obstruction can decreasesmell sensationsby limiting
595
airflow to the olfactory receptors. Besides the obstructive
effect, lesions located in the upper nasal vault and/or crib-
riform plate region may also directly damagethe olfactory
epithelium and olfactory neurons (Kern, 2000). The com-
mon peripheral sinonasaltract causesof olfactory deficits
include infections, tumors, allergic rhinosinusitis, congen-
ital or developmentalabnormalities, etc.
A. Sinonasal Infectious Disease
Paranasalsinusitis is a relatively common disorder affecting
approximately 307oof the population at some time in their
lives (Allphin et al., 1991). One of the common symptoms
of acute and chronic paranasalsinusitis is decreasedsmell
sensation,which is generally reversible.The prompt diag-
nosis and treatment of sinusitis are important for restoring
olfactory function. Though the exact causeof chemosensory
dysfunction secondaryto sinusitis is elusive, alterationsin
nasal air flow and mucociliary clearanceor obstruction from
secretoryproducts,polyps, or retentioncystsmay contribute
to olfactory dysfunction (Loury and Kennedy, 199i).
In the diagnosis and evaluation of paranasal sinusitis,
medical imaging plays an important role. At present,high-
resolution CT is the preferred imaging technique,preceded
by nasal endoscopicexamination. Radiographicmanifesta-
tions of sinusitis have been well documented. In general,
air-fluid levels are usually indicative of acute sinusitis,
whereas mucoperiosteal thickening or sinus opacification
can be seen in acute and chronic disease.Polyps, mucous
retention cysts, sinus expansion, and bony thickening of
the walls of the sinus might also indicate chronicity of dis-
ease. CT is an excellent modality for the evaluation of
bony abnormalities, such as osteitis or remodeling. seenin
some inflammatory lesions. CT also will identify the
infundibulum, the maxillary sinus ostium, the middle mea-
tus, the uncinate process, and the individual ethmoid air
cells that make up the ostiomeatal complex. This will help
the functional endoscopic sinus surgeon in his ability to
plan effective surgery to restore normal mucociliary clear-
ance. On the other hand, MRI is also highly sensitive for
detecting mucosal thickening and other soft tissue abnor-
malities (Shapiroand Som, 1989).By and large, inflamed
mucosais usually high in signal intensity on T2-weighted
MR imagesand low in intensityon T1-weightedscans.The
signal intensity of the sinus secretionswill vary with the
concentrafion of protein within the sinus (Barat, 1990;
Drutman et al. 1991; Shapiroand Som, 1989).
B. Tirmors of the Nasal Cavity and Paranasal Sinuses
Neoplasmsof the sinonasaltract are uncommon. Malignant
tumors ofthe nasalcavity and paranasalsinusesaccountfor
596
only 0.2-0.87o of all human malignancies(Som, 1991).
Early symptoms of sinonasal tract tumors, such as nasal
discharge,unilateral nasal obstruction, and minor intermit-
tent epistaxis, may simulate low-grade chronic infection.
Subsequentsymptoms depend on the tumor's location and
pattern of growth. Neoplasms arising in the upper nasal
cavity and extending through the cribriform plate or into
the ethmoid sinuses are often accompanied by frontal
headache,visual disturbances,and decreasedsmell sensa-
tion. Almost all sinonasaltract tumors and tumor-like con-
ditions that grow to a large size may cause a decline in
olfactory acuity by interfering with patencyof the nasal air-
way or directly destroyingthe olfactory receptors.The most
common malignancies of the sinonasal system are squa-
mous cell carcinoma and adenocarcinoma,but lymphoma,
melanoma, adenoid cystic carcinoma, and chondrosarco-
mas also populate the nasal cavity. Two examplesof intrin-
sic sinonasaltract tumors relatively unique to the sinuses
(the olfactory neuroblastomaand the inverted papilloma,
both of which often causehyposmia or anosmia)may serve
as prototypes for massesin this region.
1. OlfactoryNeuroblastoma
Olfactory neuroblastoma, or esthesioneuroblastoma,is a
rare nasal tumor originating from the olfactory neuroepi-
thelium lining the roof of the nasal vault and in close prox-
imity to the cribriform plate. There have been less than
300 reported casesin the world literature. Olfactory neu-
roblastomasoccur in all age groups with a peak incidence
in the 11-20 and 51-60 year groups. There is a slight pre-
ponderance of the tumor in women. The incidence of
olfactory neuroblastomahas been estimated to range from
2 to 3Eoof all malignant inffanasal neoplasms.The most
common symptoms are unilateral nasal obstruction and
recurrent epistaxis. Hyposmia or rhinorrhea is not
unusual. Extension into the orbit, paranasal sinuses, or
anterior cranial fossa may cause vision disturbances and
headache(Elkon et a1.,1979;Li et al., 1993;Newhill et al.,
1985). In the detection and staging of olfactory neuroblas-
toma, CT and/or MRI play an important role. Generally
speaking, MRI is more accurate than CT in showing the
tumor's intracranial extent. MRI is also exquisitely useful
for differentiating neoplasm from postobstructed secre-
tions because of the difference in the signal intensity
(secretions are bright on T2, tumor intermediate).
Unfortunately, signal intensity characteristics of various
sinonasal tract tumors overlap each other, so MRI cannot
usually predict specific tumor histology. However juvenile
angiofibroma can usually be distinguished from other
tumors on the basis of its high vascularity and marked
enhancement.
Li et al.
A recently described imaging finding characteristic
of olfactory neuroblastomasis the presenceof peripheral
peritumoral cysts along the intracranial portion of the
tumor. If stippled calcifications are also seen on CT, the
diagnosisis assured.
2. Inverted Papillomas and Other SinonasalTumors
The inverted papilloma is a relatively rare and locally
aggressivesinonasal tumor. It constitutes 0.547o of pri-
mary nasal tumors and occurs predominantly in males in
the fifth and sixth decadesof life (Phillips et al., 1990).
The most common presenting symptoms are nasal
obstruction,epistaxis,and hyposmia.Subsequentsinusitis
and tumor extension into the sinusesand orbits can cause
purulent nasal discharge,pain, and diplopia (Som, 1991).
Radiographic findings of inverted papilloma can vary
from a small nasal polypoid nodule to an expansile large
mass, which may remodel the nasal vault and extend into
the sinuses.orbits. or even the anterior skull base. CT and
MRI are very useful in defining the location and extension
of the tumor (Buchwald et al., 1990;Yousemet al., 1992)
(Fig. 1.). Calcification is not uncommon in this tumor.
Other sinonasaltract tumors, such as squamouscell car-
cinoma, adenocarcinoma,melanoma, etc., can also cause
hyposmia or anosmia during their late stage. Squamous
cell carcinoma accountsfor 8O7oof paranasalsinus malig-
nances,is most commonly seenin the maxillary sinus, and
usually demonstratesbone destruction at the time of pre-
sentation.Adenocarcinomas occur most frequently in the
ethmoid sinus while melanomais usually seenintranasally.
Additional benign neoplasms known to affect the
sinonasalcavity include osteomas,enchondromas,schwan-
nomas, and juvenile angiofibromas. Osteomasare usually
identified in the frontal sinus and may be a sourcefor recur-
rent headacheand/or recurrent sinusitis. The classic story
of a frontal sinus osteomanarrowing the sinus opening is a
patient who has severesinus pain associatedwith takeoffs
from airplane flights. This is a benign mass,which is often
completely invisible on MRI due to the presenceof dense
compact bone making up the mass.On the other hand, it is
easily identified on CT as a markedly hyperdense bony
mass protruding in the sinus. Occasionally, the osteoma
will result in mucocele formation and./orpneumocephalus
as the posterior wall of the frontal sinus is breached.
Enchondromas are less common neoplasms of the
sinonasalcavity which, on CT, often have a popcorn calci-
fication appearancedifferent from the stippled calcifica-
tion of inverted papillomas. This lesion, because of its
characteristiccalcification, is best evaluatedwith CT.
Schwannomas of the fifth cranial nerve are the most
common to affect the sinonasal cavity. They will typically
Medical Imaging of Olfactory Deficits 597

Figure 1 A 40-year-old woman with 3-month history of decreasingsmell sensationand left nasal obstruction. (A) Bone-targetedcoro-
nal CT shows an expanded opacified left nasal cavity with bowing of the lateral nasal wall (arrows) and opacification of the left maxil-
lary and both sphenoid sinuses. (B) Axial contrast-enhancedCT scan shows erosion through the left lamina papyracea (arrow) with
displacement of the medial rectus and globe laterally. The differentation between tumor and obstructed secretionsis not readily apparent
with CT. Histological diagnosis: nasal cavity carcinoma arising within a dysplastic inverted papilloma.

follow the course of the nerve and can expand skull base
foramina through which they travel. The signal intensity of
schwannomas varies according to the content of the dense
Antoni A tissue or loose Antoni B tissue, the latter being
brighter on T2W scans. Schwannomas enhance avidly,
although they may have inhomogeneity to the enhancement.
Finally, one has the juvenile angiofibroma, a fascinating
benign neoplasm, which appearsto arise in the region of
the sphenopalatine foramen and/or the pterygopalatine
fossa The lesion accounts for O.5Voof head and neck
massesand is typically seenin adolescentmales who pre-
sent with epistaxis and/or a nasal mass (Mehra, 1989). The
lesion is highly vascular as exemplified on MRI by the sig-
nal flow voids within the lesion and its marked contrast
enhancement.Becauseof its propensity for spreading via
the canals and foramina at the skull base,MRI is probably
the study of choice for the evaluation of this neoplasm.
Embolization of these lesions will assist the surseon in
limiting blood loss if resection is considered.
3. Malignant Neoplasms
CT and MRI probably play complementary roles in the
evaluation of sinonasal malignancies because of CT's
superiority in defining bony margins and MRI's superior
soft tissue resolution and ability to define intracranial or
intraorbital spread. One of the advantagesof MRI is the
ability to distinguish sinus neoplasm from postobstructive
secretions. This may be difficult by CT if the sectetions are
isodense to the mass and if the malignancy does not
enhance dramatically. If one was forced to study the
patient with a single modality, the literature supportsMRI
as the best study for the staging of sinonasalmalignancies
(Hunink et al., 1990; Kraus et al.,1992; Paling et al.,1987;
Sissonet al.. 1989).
Som et al. (1991) noted that squamouscell carcinoma
(low in T2 intensity) could be distinguished from inflam-
mation (high in T2 intensity). They compared CT to MRI
for mapping sinonasal tumors. They found that MRI and
CT were equivalent in 23 of 53 patients in defining tumor
extent and that MRI was superior to CT in 26 patients. Of
the 4 casesin which CT was superior, subtle bony erosion
(2) andosteo(1)-cartilaginous(1) lesionsaccountedfor the
"misses" on MRI. Of 60 inflammatory lesions, MRI was
superior (Bonte et al., 1993) or equivalent (Everall et al.,
1991) to CT in all cases.Inflammation (bright) and neo-
plasm (intermediate) could be distinguished in 95Vo of
casesbased on T2W signal intensity. Even when the sinus
secretionsbecome increasingly inspissatedand the signal
intensity on T2W scansdecreases,the neoplasmcan be dis-
tinguished from the obstructed secretions by its typical
heterogeneity as opposed to the smooth homogenous
598
appearanceof sinus secretions. This is also true in the
casesof mucoceles, which may occur after or in associa-
tion with sinus neoplasms.Additionally, MRI has shown
that most squamouscell carcinomas of the sinonasalcav-
ity enhancewith gadolinium in a solid fashion as opposed
to a peripheral rim of enhancement in sinus secretions
and/or mucoceles.Unfortunately, lymphomas, undifferen-
tiated carcinomas, inverted papillomas, and some sarco-
mas may have identical signal intensity and enhancement
characteristicsas squamouscell carcinoma.
Gadolinium is particularly useful for demonstrating
epidural or meningeal invasion of neoplasms.Often, post-
contrast scans must be combined with fat suppression
techniques in order to identify enhancement amidst the
abundantskull basefat. In one series,'l57o of patients with
intracranial extension of sinonasalmalignancies had addi-
tional information about tumor extent demonstratedwith
postcontrastMRI studies (van Tassel et al., l99l).
Subtraction MRI of pregadolinium scans from post-
gadolinium scans may improve visibility of such subtle
enhancement(Lloyd and Barker, 1991). It should be noted
that meningeal enhancementneed not necessarily imply
neoplastic invasion; just as in cases of meningioma, the
dura may enhance because of reactive fibrovascular
changesalone.
When one encountersa sinonasal mass that is eroding
intracranially, one must consider carcinoma,olfactory neu-
roblastoma, sarcomas,lymphomas, sinonasalpolyposis,
and inverted papillomas. Twelve percent of patients with
polyposis and mucoceles eventually erode the skull base
(Som et al., l99l). The pattern of bone destruction may be
similar between malignant and benign lesions at the
non-sinus bearing skull base. Bone remodeling in this
location is a rarity; a permeativepattern is the norm for all
lesions.Som et al. (1988)have suggestedthat a lesionwith
homogeneous signal intensity invading intracranially is
more likely to be a malignancy, whereas heterogeneity
suggestsan inflammatory cause. Unfortunately, necrosis,
hemorrhage,or calcification in carcinomas,olfactory neu-
roblastomas,or sarcomasmay cause signal heterogeneity.
Polyps generally enhancein a peripheral pattern; true neo-
plasms enhance solidly. Malignancies have a broad flat
base of skull erosion; benign conditions have a rounded
polypoid intracranial excrescence.
Squamous cell carcinomas account for 807o of
the malignanciesto affect the paranasalsinusesand807oin
the maxillary sinus. The hallmark of malignancies of the
sinonasalcavity is bony destruction, seenin approximately
80Voof CT scansof sinonasalsquamouscells carcinoma at
initial presentation.The lesion is confined to the maxillary
antrum in only 25Vo of cases at presentation (Lyons and
Donald, 1991). In most series documentins sinonasal
Li et al.
squamous cell carcinoma signal intensity characteristics
on MRI, the lesion is characterizedby a low signal inten-
sity on T2W scans. This is why differentiation with
obstructed secretionswhich are typically bright in signal
intensity on T2W scansis so easy on MRI.
Becauseof Som et al.'s early work depicting sinonasal
malignancies as hypointense on T2W scans, people have
come to rely on this pulse sequencefor mapping cancers
(Som et al., 1990). Unfortunately, low intensity on T2W
scansis an inconstant finding in sinonasalmalignancies in
general. Hunick et al. found that over 50%oof head and
neck malignancies had signal intensity on T2W scansthat
was brighter than muscle and isointense to brain (Hunink
et al., 1990).Approximately 25Voof benign tumors had the
same intensity pattern. Lanzieri et al. (1991) also reported
that the signal intensities of tumors, mucoceles, schwan-
nomas, and obstructedsecretionsmay show some overlap.
Som et al. (1991) have found that minor salivary gland
massesand schwannomasmay have T2W signal intensity
similar to that of inflammatory lesions. Minor salivary
gland tumors and melanoma are the next most common
malignancies to affect the sinonasalcavity after squamous
cell carcinoma(van Tasselet al., 1991).The minor salivary
gland tumors representa wide variety of histological types
including adenoid cystic carcinoma, mucoepidermoid car-
cinoma, adenocarcinoma,and undifferentiated carcinoma.
Of these tumors, adenoid cystic carcinoma is the most
common variety. Its signal intensity may be high or low on
T2W scans, possibly related to the degree of tubular or
cribriform histological pattern as well as cystic spaces,
necrosis, and tumor cell density. Tissue specificity is not
readily achievablewith MRI or CT. Gadolinium is of par-
ticular use with adenoid cystic carcinomas, which have a
propensity for perineural spread(Graamansand Slootweg,
1989). With sinonasal cavity malignancies one should
always attempt to trace back the branchesof the fifth cra-
nial nerve via the pterygopalatine fossa, foramen rotun-
dum, foramen ovale, and orbital fissures in order to
identify perineural neoplastic spread.
Adenocarcinomas of the paranasal sinuses have a
predilection for the ethmoid sinusesand appearmore com-
monly in woodworkers. This tumor also tends to have low
signal intensity on T2W MRI images but may have high
signal intensity in a small percentageof cases.
Sarcomas of the sinonasal cavities are very rare, with
chondrosarcomabeing the most common. Again, the his-
tological diagnosis is probably better suggested by CT
based on the characteristic whorls of calcification.
However, for staging, MRI is competitive with CT, and,
particularly if repeat examinations are going to be
required, follow-up with MRI to avoid the radiation expo-
sure of CT is recommended.
Medicat Imaging of Olfactory Deficits
Melanoma is a tumor that is usually identified in the
nasal cavity as opposed to the paranasalsinuses.It has
been associatedwith melanosis in which there is field
deposition of melanin along the mucosal surface of the
sinonasal cavity. Therefore, multiplicity of lesions
becomes a problem when dealing with melanomas'
Neither CT nor MRI is particularly helpful in identifying
the field "cancerization" of melanoma.When melanoma
contains melanin there is paramagnetismwhich causes
T1 and T2 shortening accounting for high signal intensity
on T1W scans and low signal intensity on T2W scans
(Atlas et a1., 1990). However, an amelanotic melanoma
may have bright signal intensity on T2W scans.The pres-
ence of hemorrhage associatedwith the melanoma, a
common occuruencebecauseof the coincidenceof epis-
taxis, may further obfuscate the signal intensity pattern
( Y o u s e me t a l . . 1 9 9 6 c ) .
Lymphoma does occur in the paranasalsinusesand may
have variable signal intensity as well. It is characterizedby
homogeneous signal intensity without necrosis and the
associationwith cervical lymphadenopathy.
Metastatic diseaseto the paranasalsinusesis extremely
rare. Of the primary causesof metastasesto the sinuses,
renal cell carcinoma is probably the most common. This
tumor also has a propensity for hemorrhageand may also
have a variable signal intensity depending upon the stage
of hemorrhage.
C. Allergic Reactions
Allergic rhinitis is a common upper airway condition
affecting about 30 million Americans with peak prevalence
in the age group from 35-54 years (Baroody and Naclerio,
1991). Hyposmia or anosmia is common with allergic
rhinitis, mainly caused by nasal obstruction by polyps or
inflamed mucosa, which limit accessof inspired air to the
roof of the nasal vault (Cowart et al., 1993). The diagnos-
tic work-up begins with a careful history, which attempts
to identify offending allergens. Skin testing of specific
antigens is often used to confirm the diagnosis. Medical
imaging studies play a supplementaryrole in the evalua-
tion of sinonasal airway status and differential diagnosis.
CT and MRI are also important for detecting any compli-
cations such as sinusitis, mucoceles,and aggressivepolyps
in patients with allergic rhinitis. Rounded excrescences
and enlargementof ostia are seenin the airway of patients
with polyposis.
D. Congenital or Developmental Abnormalities
It is generally acceptedthat normal variations in the nasal
anatomy may play a role in preventing the access of an
599
odorant to the olfactory receptor area. The senseof smell
is probably less than normal in many patients with cranio-
facial anomalies (Crysdale, 1981). Congenital develop-
mental abnormalities include choanal atresia, hereditary
nasal septal deviation, facial hypoplasia, cleft palate, nasal
dermoids and epidermoids,cephaloceles,and gliomas, etc.
Medical imaging techniques, especially high-resolution
CT, play a key role to detect and evaluate the facial and
bony changes(Barkovich et a1.,7991; Klein et a1.,1987).
CT is most useful because surgical correction requires
identification of and closure of the osseousabnormalities.
MRI is most effective in defining soft tissue massessuch
as cephalocelesand nasal gliomas.
Congenital anosmia can be associatedwith a number of
developmental and inflammatory conditions. Kallmann's
syndrome, also known as hypogonadotrophic hypogonadism
with anosmia, is a congenital X-linked disorder in which the
olfactory bulbs and tracts are not formed. This is not associ-
ated with holoprosencephaly, and the usual deficits are
related to hormonal abnormalities in the pituitary gland with
the loss of senseof smell. Infertility often coexists.In 1993,
an MR study of the olfactory system in Kallmann's disease
showedabsenceofthe olfactory bulbs and tracts in 17 of 18
patients while confirming the presenceof the olfactory bulbs
and tracts in all 10 studied patients with idiopathic hypo-
gonadotropichypogonadism(Yousem et al., 1993, 1996a).
Some patients have absenceof the olfactory bulbs and tracts
without Kallmann's syndrome. It is unclear whether this rep-
resentscongenital absenceor whether an inflammatory con-
dition early in infancy destroys the olfactory bulbs and tracts.
Certain viruses have a propenslty for injuring the olfactory
system.A recent study has noted the incomplete formation of
olfactory sulci in patients with congenital anosmia as well as
a variable percentage of aplastic olfactory bulbs, ffacts, and
tubercles (Di Rienzo et al., 2002). Still others may have con-
genital absenceof senseof smell on the basis of early head
trauma where the ciliary nerves as they crossedthe cribiform
plate may be sheared and the olfactory system is affected.
Infectious causesmay also affect the senseof smell in early
childhood, usually secondarilyto viruses.In thesecasesone
seesthe olfactory bulbs and tracts; but they are not functional.
Holoprosencephaly is a congenital, multiple midline
malformation disorder that has a known association with
sensorydeficits of vision and olfaction. Although variable
amounts of aplasia and hypoplasia of the olfactory appura-
tus may be identified, the most common MR finding is
complete absenceof the olfactory bulbs, occurring in 92Vo
of patients. A high association with absenceof the olfac-
tory nerves and tuberclesis also seen.There does appearto
be some, albeit poor, differentiation of the olfactory sulci
and gyri recti, which were absentonly in a little over half
of the subjects (Barkovich and Quint, 1993).
600
E. Other Peripheral Causes
It is estimated that 30 million Americans have used
cocaine and 5 million use it regularly (Gregler and Mark,
1986). Intranasaluse of cocaine and heroin has reached
epidemic proportions in the United States. Although
hyposmia or anosmia has been suggestedto occur often
in cocaine abusers, few studies using quantitative mea-
sures of olfactory function have confirmed such reports.
A sole study on this topic reported that of I I cocaine
abusers who underwent detailed olfactory testing, only
one was found to be anosmic and another had mild olfac-
tory discrimination dysfunction (Gordon et al., 1990).
These authors note that most cocaine abusers do not
develop permanent olfactory dysfunction. If, in fact,
olfactory disturbance occurs as a result of heavy cocaine
use, it could be due to associatedconductive disorders,
nasal airway obstruction, alteration in sinonasal aerody-
namics, damage to the olfactory epithelium, damage to
the central olfactory system, or osteolysis of the cribri-
form plate (Kuriloff, 1989).
Concerning the conductive disorders, severalreports of
osteolytic sinusitis and extensiveosteocartilaginousnecro-
sis of the nasal septum in cocaine abusers have been
described (Newman, 1988; Schweitzer, 1986\. Erosion of
nasal septal cartilage is a known complication of cocaine
abuse. Within the differential diagnosis for cartilaginous
destruction, one should include Wegener'sgranulomatosis,
syphilis, leprosy, lymphoma, rhinoscleroma (a klebsiella
infection), and fungal invasion. CT, preferably in the coro-
nal plane, can provide excellent views of septal perfora-
tion, osteolysis, and sinusitis.
To evaluate intracranial disorders associated with
cocaine, MRI is the study of choice. Vasculitic infarcts,
hypertensivehemorrhages,and white matter ischemic foci
may be seen with MRI. Recently Tumeth and colleagues
demonstrated multifocal cortical deficits with a special
predilection for the frontal and temporal lobes on SPECT
perfusion brain scansin chronic cocaine abusers(Tumeth
et al., 1990). Similar findings have been reported by others
(Holman et al., l99l1, Kolow et al., 1988). These findings
may suggest a central basis for some cases of cocaine-
related decreased olfaction. Some studies also have
revealed that cerebral atrophy developsin chronic cocaine
abusersandthat the severity correlateswith the duration of
abuse(Pascual-Leoneet al., 1991).
Anosmia or hyposmia is a frequent sequelaof high-
level midface fractures in which the olfactory nerves
may be severed at the level of the cribriform plate
(Kassel, 1988; Mathog, 1992). Because ethmoid com-
plex and cribriform plate fractures are difficult to detect
on plain radiographs,thin-section coronal CT is the best
Li et al.
measure to assessnaso-ethmoid trauma (Daly et al.,
1990;Kassel,1988).
V. CENTRAL CAUSES OFOLFACTORY
DISEASES
There are numerous CNS disorders that are associated
with olfactory dysfunction. The most common types fall in
the categoriesof degenerativeneuropsychiatric disorders,
hereditary conditions, trauma, and central neoplasms. Of
course, in some disorders the involvement of both periph-
eral and central neural processesmay occur.
A. Alzheimer's Disease
It has been well documentedthat olfaction is significantly
altered in Alzheimer's (AD). Nearly all studiesof olfactory
function in patients with AD have reported decreasedsmell
relative to age-matchedcontrols (see Chapter 23). These
studies demonstratemarked impairment of smell function
in early AD, whether measuredby identification, discrim-
ination, or threshold sensitivity (Doty, 1991; Doty et al.,
1987;Serbyet al., 1991).
Recent neuropathological studies have correlated well
with these clinical f,rndings.The anterior olfactory nuclei
in AD patients contain senile plaques, neurofibrillary tan-
gles, granulovascular degeneration, and cell loss
(Averback, 1983; Esiri and Wilcock, 1984). The olfactory
bulbs also show involvement (Esiri and Wilcock, 1984:
Ohm and Braak, 1987), as does nasal sensory epithelium
(Jafek et al., 1992). In addition, central olfactory struc-
tures, especially the amygdala and the entorhinal, pyri-
form, and temporal cortices, are frequently affected by
Alzheimer's disease(Harrison, 1986; Pearsonand Powell,
1989). Besides the above findings, devastating nerve cell
loss and gliosis in the region of the hippocampal formation
have been observed at autopsy in AD patients (Ball et al.,
1985;Hyman et al., 1984).
Neuroimaging has played an important role in detecting
some of the pathological changesof AD patients in vivo,
and its uses are growing, both for clinical evaluation and as
a researchtool. Early CT studies in AD patients demon-
strated generalized enlargement of the ventricular system
and sulci (George et al, 1981; Naser et a1., 1980). Several
reports have noted that ventricular and sulcal enlargement
correlatewith the severityof AD (Albert et al., 1984;George
et al., 1983). However, these findings are not specihc and
have relatively weak conelations. de Leon and colleagues
(1989) have emphasizedthe rate of change in ventricular
size with repeatedCT scansas an important index in the
diagnosisof AD. Recently,severalinvestigatorshave recog-
Medical Imaging of Olfactory Deficits
nized that CT andlor MRI delineation of atrophic changesin
the temporal lobe and the hippocampus with enlargement of
hippocampal-choroidalfissuresstrongly supportthe diagno-
sis of AD (de Leon et al., 1988;Georgeet al., 1990;Kesslak
et a1.,7991;Kido et al., 1989).
McDonald and colleagues(1991) reviewedMRI scansin
22 patients with early-onset AD. The results showed that
patients with AD were significantly more likely than age-
matched controls to have MR evidence of periventriculm
hyperintensities on T2W scans.This study suggestedthat the
increased frequency of periventricular hyperintensities may
have a relationship to the diseaseprocess.Our own experi-
ence with MRI studies of AD patients is that most of the
cases with AD have, in addition to ventriculomegaly and
sulcal widening, significantly reducedvolume of the tempo-
ral lobe and slight atrophy ofolfactory bulbs. (Fig. 2).
Besides CT and MRI, SPECT and PET techniques are
also useful for evaluating regional cerebral blood flow,
Figure 2 A 60-year-old woman with Alzheimer's disease.
UPSIT scores revealed severe bilateral anosmia. (A) Normal
olfactory bulbs are seen (arrows) on coronal MR. Dilation of the
olfactory sulci (arrowheads) reflects generalized atrophy. (B)
Coronal MR scan through the temporal lobes shows temporal
horn enlargement and atrophic changes, slightly worse on the
rieht side.
601
regional oxygen, and glucose metabolism, which may pro-
vide evidence supportive of the diagnosis of AD (Jagust
and Eberling, l99l). The above-mentioned structural
atrophic changes by CT and MRI are also supported by
functional imaging studies (McDonald et al., 1991;
Ohnishi et al., 1991). The major findings of functioning
imaging studies in patients with AD are abnormal regional
cerebral blood flow pattern and flow reduction. The com-
mon sites of blood flow reduction are in the temporopari-
etal region and the frontal areas.In one report (Bonte et al,
1993), sevenpatients with possible diagnosis of AD stud-
ied by SPECT showed only frontal flow abnormalities. Is
this an early imaging finding which may suggesta patho-
physiologic basis to explain the decreasingsmell sensation
in AD? Of course,more studies are neededfor further dis-
covering the nature of AD. We believe that early and cor-
rect diagnosis of AD in vivo by neuroimaging techniques
will be possible in the near future.
There is a dose-related association between apolipopro-
tein E-4 (APOE-4) allelic frequency and the development
of AD (APOE-2 may confer protection)' Recent studies
have shown a decline in resting parietal, temporal' and pre-
frontal PET glucose metabolism in cognitively intact
patients with APOE-4. It remains to be seen whether this,
and/oran analogousfMRI study, may serve to be a predic-
tor of development of AD.
Recently some investigators have used dynamic con-
trast susceptibility contrast imaging MR to try to duplicate
the nuclear medicine flow studies.Indeed they have found
that relative values of temporoparietal regional cerebral
blood volume (as a percentageof cerebellar CBV) were
reduced by a factor of 2OVobilaterally in the patients with
Alzheimer disease compared to normals. Using left and
right temporoparietal rCBV as index measures,specificity
was 96Voand sensitivity was 95Vain moderately AD and
88/o in mild AD (Hanis, 1998).
B. Parkinson's Disease
Odor detection and identification are significantly
impaired in Parkinson's disease(PD) patients (Doty et al.,
1988, 1995; Montgomery et al., 2000) (see Chapter 23). It
is unclear whether the olfactory dehcits in PD and AD
share the sarne cause. Not surprisingly, PD research into
the causeof smell dysfunction has focused on dopaminer-
gic changes.Brooks and colleagues (1991) have demon-
strated by using PET that patients with PD show
significantly reduced mean uptake of l8F-dopa in the cau-
date and putamen, especially in the posterior part of the
putamen. Previous functional imaging studies have also
indicated a reduction of striatal dopamine storage in PD.
 602
PET technique with l8F-dopa in pD patienrs has also
demonstrated reduced basal ganglia activity (Alavi and
Hirsch, 1991). However, the olfactory deficit is unrelated
to severity of motor or cognitive symptoms and is not
improved by l-dopa therapy (Doty et al., 1992), so the
underlying causes of olfactory dysfunction in pD still
requires more study.
CT scanning has little role in establishingthe diagnosis
of PD other than to exclude mass lesions in the brain. In
general, CT shows no specific striatal abnormalities and
occasionally only mild, nonspecific ventricular and sulcal
enlargement.The major feature of pD on MRI appearsto
be a trend towards a decreasedwidth of the pars compacta
of the substantianigra (Braffman et al, 1989). There is a
lateral to medial gradient of loss of the normal signal of the
pars compacta as well as volume loss. Moderate or marked
cortical atrophy tends to occur more frequently in pD
patients than in controls. MRI may occasionally show
abnormal decreasedT2W intensity in the putamen and to a
lesser degree in the caudate nuclei and substantia nigra,
suggestiveof iron deposition (Drayer et al, 1986).
C. Huntington'sDisease
Patients with Huntington's disease (HD) evidence olfac-
tory dysfunction (Doty, 1991; Moberg et al., 1987).
Neuropathological studies in HD have demonstratedpre-
mature neuronal cell death and reactive gliosis occurring
most markedly in the head of the caudatenuclei bilaterally
(Myers et al., 1991; Vonsattel et al., 1985). A loss of
1A-807o of the striatal neurons may occur before func-
tional impairment is obvious. Similar but less extensive
changesalso affect the putamen.Later, atrophy of the cere-
bral cortex occurs as well. All of theseprogressiveatrophic
changescan be identified on CT and MRI scans,especially
in the caudate nuclei, where the volume of the caudate
head decreases and the intercaudate distance increases
(Simmons et al., 1986; Starksteinet a1.,1989). Increased
signal intensity in the putamen and globus pallidus has
been described in the juvenile form of Huntington's dis-
ease,and frontal atrophy is usually present.
PET studies of patients with HD have consistently
demonstratedhypometabolism in the caudatenuclei, often
before the development of atrophy on CT (Hayden et al.,
1986). SPECT studies involving HD patients have also
revealed decreaseduptake in the caudatenuclei, including
the caudatesof one patient with early diseaseand no evi-
dence of atrophy on MRI (Nagel et al., 1988; Reid et al.,
1988). Thus, functional imaging with PET or SpECT may
contribute to the early diagnosis of HD.
Theoretically, the input of caudate/putaminalfibers to
the limbic system and striatum may be altered, leading to
Li et al.
olfactory dysfunction, but the exact mechanismfor hypos-
mia in HD patients remains to be worked out.
D. Korsakoff'sPsychosis
Patientswith Korsakoff's psychosis (Kp) exhibit impaired
odor detection, identification, and intensity estimation
(Joneset a1.,1975; Mair et al., 1986).An animal model
study has shown that the behavior of rats recovedng from
pyrithiamine-induced thiamine deficiency share several
important features with KP patients, including the impair-
ments observed for smell, hearing, learning, and memory
(Mair et al., 1991). The mechanism of hyposia and/or
dysosmia in patients with KP is unclear and still under
investigation. Olfactory perception may be selectively
impaired in KP by the diencephalonlesions that are char-
acteristic of this disease.Degenerationin the mediodorsal
thalamic nucleus (the common neuropathologicallesion in
KP) and atrophy in the prefrontal areasmay also causethe
olfactory dysfunction (Mair et al., 1986).
A quantitative neuropathological study of the human
cerebral cortex has shown that the number ofcortical neu-
rons in the superior frontal lobe in chronic alcoholic
patients is significantly reduced (Happer et al., 1987).
Chronic alcoholism is also associatedwith smaller vol-
umes of cortical white and gray matter relative to controls
(Pfefferbaum et a1.,1995). Traditional neuropsychological
tests and functional imaging studies have also demon-
strateddisturbancesof frontal-lobe function and metabolic
deficits in patients with KP (Joyce and Robbins, l99l;
Kopelman, 1991;Metter et al., 1989).
Brain CT scans have demonstrated that KP patients
show more pronouncedthird and lateral ventricular dilata-
tion and wider interhemispheric fissures than matched
groups of normal controls and non-Korsakoff alcoholics
(Jacobsonand Lishman, 1990; Ron, 1983; Ron et al.,
1982). Shrinkage in the frontal lobes and cerebellum
appears to be especially pronounced (Jacobson and
Lishman, 1990).A MRI study (Jerniganet al., 1991) has
revealedthat patients with KP show widespreadreductions
in gray matter volumes in addition to CSF increases,with
the greatestreductionsobservedin diencephalic structures.
The volume losses that best differentiate the KP patients
from the alcoholic controls included lossesin anterior por-
tions of the diencephalon,mesial temporal lobe structures,
and orbitofrontal cortices (areasinvolved in olfaction per-
ception). Several other studies (Donnal et al., 1990;
Gallucci et al., 1990; Squire et al., 1990;Victor, i990) have
also demonstratedthat MRI is highly sensitivein detecting
reversible diencephalon (medial thalamic) and mesen-
cephalic (periaqueductal) lesions. In addition to general-
ized cortical and cerebellar vermian atrophy seen on CT
Medical Imaging of Olfactory Deficits
and MR, recent reports have noted the presenceof high
signal intensity areasin the periaqueductalgray matter of
the midbrain (40Vo),the paraventricular thalamic regions
(46Vo),the mamillothalamic tract, and in tissue surround-
ing the third ventricle on T2W MR scans (T2WI).
Reversible thalamic lesions in the dorsal medial nuclei
have also been reported. These areas may or may not
enhance(in some casesthe enhancementmay be dramatic,
almost sarcoid-like) and may be associatedwith mamillary
body atrophy. Mamillary body enhancementmay be the
sole manifestation of Wernicke's encephalopathy.Myelin
degeneration, mamillary body volume loss, intracellular
edema,and microglial proliferation are seenpathologically
(but may be presentin alcoholics without Wernicke's).
MRI findings in patients with KP may enable early
diagnosis of the disease,which may have a positive effect
on both treatment and prognosis (Gallucci et al., 1990).
E. Schizophrenia
Impaired olfactory function has been reported in schizo-
phrenics,especially males (seeChapters23 and 24). These
olfactory deficits, which are not of the samemagnitude as
those seenin AD and PD, are perhapsnot unexpectedgiven
the occurrenceof olfactory hallucinationsas symptomsin a
number of patients with schizophrenia and the evidence
linking both to temporal lobe dysfunction (Rausch et al',
1977; Roberts, 1988). Neuropathologicalstudiesin schizo-
phrenic patientshave reported neuronal loss in the entorhi-
nal region and prefrontal cortex, gliosis in the basal limbic
structures of the forebrain, and atrophy in temporolimbic
structures (Benes et al., 1986; Falkai et al., 1988).
Neurophysiological function studies (including regional
cerebral blood flow, brain electrical activity mapping, and
regional metabolic activity in the brain) in patients with
schizophrenia have demonstrated prefrontal cortex and
temporal lobe dysfunction (Mesulam, 1990). Functional
imaging, such as PET or SPECT, in the study of schizo-
phrenia is limited and inconclusive. However, functional
imaging has provided some evidence that certain schizo-
phrenic patientshave decreasedblood flow and metabolism
in the frontal lobes (hypofrontality) (Alavi and Hirsch,
r99r).
Anatomical imaging findings have basically paralleled
the neuropathological changes in the brains of patients
with schizophrenia. The most consistent finding on both
CT and MRI is an increase in the size of the cerebral ven-
tricular system, especially in the frontal and temporal
horns, and corresponding decreasesin cerebral tissue,
especially in the prefrontal cortex and in medial lem-
porolimbic structures (Mesulam, 1990; Suddath et al.,
1989;Young et al., 1991). Suddathand colleagues(1989)
603
evaluatedthe volume of the temporal lobes in schizophre-
nias by a quantitative MRI study. The results showed that
the volume of temporal lobe gray matter was 20Vosmaller
in the patients than in the control subjects,and lateral ven-
tricular volume was 677olarger in the schizophreniagroup
than in the control group. Schizophrenic patients tend to
have smaller hippocampi that matched controls. schizo-
phrenias are also reported to have cavum septum pellu-
cidum more frequently than controls. In a recent study,
Turetsky et al. (2000) reported that patients with schizo-
phrenia exhibited 23%o smaller olfactory bulb volume
bilaterally than comparison subjectsby a quantitative MRI
study.
E CongenitalAnosmia
Congenital anosmia, which traditionally has been defined
as anosmia present from a patient's earliest recollection,
has been recognizedfor centuries.The most common form
of congenital anosmia is Kallmann's syndrome or olfac-
tory dysplasia, which is characteized by hypo-
gonadotropic hypogonadism and anosmia (Kallmann et
al., 1944; Lieblich et al., 1982). The incidence of
Kallmann's syndrome is about 1:100,000 in men and
1:50,000 in women. There has been increasing interest in
the pathology, pathophysiology, and genetics of this disor-
der. Pathological and surgical studies of patients with
Kallmann's syndrome have shown agenesisof the olfac-
tory bulbs (DeMorsier and Gauthiet 1963; Males et al.,
1973). Laboratory findings include decreasedserum folli-
cle-stimulating hormone and luteinizing hormone as well
as decreasedurinary gonadotropins(Lieblich et al., 1982).
In medical imaging studies,CT is a limited tool for the
demonstration of sinonasal and intracranial abnormalities
in patients with congenital anosmia (Klein et al., 1987;
Moorman et a1., 1984). Surface coil MRI is the optimal
modality to reveal the intricate details of the olfactory
bulbs, tracts, and rhinencephalonin vivo. Klingmuller and
colleagues(1987) have clearly demonstratedthe olfactory
sulci in a normal control group by MRI, but not in the
patients with olfactory dysplasia. More recently, the
authorshave studied two caseswith Kallmann's syndrome
by MRI. Both showed no olfactory bulb at all and flatten-
ing of the gyrus recti (Yousem et al, 1993,1996a); frontal
and temporal lobe volumes were normal (Fig. 3).
In a mixed population of patents with congenital anos-
mia, we found olfactory bulb and tract absence(68-847a)
and hypoplasia (16-327o) in all 25 cases studied. Eight
individuals had Kallmann's syndrome (hypogonadotropic
hypogonadism with anosmia). Temporal andlor frontal
lobe volume loss were noted in 5 individuals, mild in all
but one individual. We concluded that congenital anosmia
 604
Figure 3 (A) Coronal 500/20 scan from normal volunteer
(64-year-old woman with normal smell function) demonstrates
normal olfactory bulbs (anows). (B) Coronal 500117 scan of
27-year-old woman with congenital anosmia without
Kallmann's syndrome shows extremely atrophic olfactory
bulbs (arrows). (C) Coronal 500/14 scan of 29-year-old male
patient with Kallmann's syndrome evidences absence of olfac-
tory bulbs and tracts with flattened gynrs rectus (arrow) on the
right side, but with normal-appearing gyrus rectus on the left
side.
or hyposmia appears to be an olfactory bulb tract phenom-
enon rather than a central process (Yousem et a1., 1996a).
Li et al.
G. Head Thauma
Craniofacial trauma can alter olfactory ability through one
of severalmechanisms:(1) damageto the nose,sinuses,or
both with resultant mechanical obstruction to odorants,(2)
shearing of olfactory filaments as they course through the
cribriform plate, (3) contusion to the olfactory bulb. and
(4) contusionor shearinginjury ofthe cerebralcortex.par-
ticularly the frontal and temporal lobes (see Chapter 30).
The incidence of anosmia or hyposmia after head trauma
has been reported quite variably from2 to 38Va,(Deems et
a1., l99l; Doty et al., 1997; Hagan, 1967; Leigh, 1943;
Levin et al., 1985; Schechterand Henkin, 1974; Summer,
1964; Ztsho, 1982) and increases with the severity of
injury (Levin et al., 1985; Summer, 1964). However, even
a minor injury can sometimesresult in anosmia or hypos-
mia (Schechterand Henkin,1974; Summer 1964). Recent
evidence has shown that the location of the hematoma or
contusion of the brain after head trauma is one of the most
important factors leading to olfactory dysfunction
(Costanzoand Zasler, 1991; Doty et al., 1997; Levin et al.,
1985; Yousem et al., 1996b). Specifically, diminished
olfactory discrimination has been confirmed in patients
with prefrontal lesions (Potter and Butters, 1980). Animal
studieshave shown that the prefrontal olfactory areaplays
a prominent role in the fine and specific discrimination of
odors (Tanabe et al., 1975). Besides prefrontal lesions,
temporal lobe structuresare also involved in the odor pro-
cessing of odor perception (Rausch and Serafetinides,
1975; Rauschet a1.,1977). Indeed frontal or temporal lobe
hematomasor contusionsare now believed to be one of the
most common causesof olfactory dysfunction after head
injury (Costanzoand Zaster, 1991; Doty et al., 1997; Levin
et al., 1985;Schellingeret al., 1993;Yousemer al., 1996b)
(Fie.a).
It has been established that plain skull radiography
plays only a small role in the evaluation of head trauma
(Masters et al., 1987). CT cunently is the study of choice
when diagnostic imaging is necessary after acute head
trauma (Cohen, 1990; Kelly et al., 1988). CT can detecr
subarachnoid hemorrhage, fractures, and intraventricular
blood, lesions for which MRI is less sensitive acutely. CT
can be performed with close patient monitoring in a rapid
fashion. However, MRI is superior to CT in the detection
and characteization of subacute injuries, hemorrhage
outside the subarachnoidspaceas in subdural hematomas,
cortical contusion, and shearing injuries. MRI is exquis-
itely sensitive to diffuse axonal injuries leading to
demyelination. MRI is also useful in the follow-up of brain
contusion and/or hemorrhage, thereby eliminating the
radiation exposure associated with CT (Cohen, 1990;
Zimmerman et al., 1986).
Medical Imaging of Olfactory Deficits
Figure 4 A 20-year-oldwomanwith posttraumaticanosmia.
(A) A smallolfactorytractis seenon the right side(arrow),but
noneis seenon the left. Severeinferior frontal lobe encephalo-
malacia is soon on this coronal TIW MR scan. (B)
Encephalomalacia is well seenon the T2W MR scan where
hyperintensesignal (S) has replacedthe inferior frontal lobes
(wheresmellprocessing occurs).
At at our institution, 25 patients with posttraumatic
smell dysfunction were evaluatedby olfactory testing and
MR. Quantitative and qualitative gradings for olfactory
bulb, tract, subfrontal region, hippocampus, and temporal
lobe damagecomelatedwith olfactory test results.Twelve
patients were anosmic, 8 had severe impairment, and 5
were mildly or impaired. Olfactory bulb and tract (88Vo
of patients), subfrontal (60Vo), and temporal lobe (32Vo)
injuries were found but did not coffelate well with olfac-
605
tory test scores (Doty et al., 1997b; Yousem et al.,
1996b). Abnormalities on MR in patients with posttrau-
matic olfactory dysfunction occur at a very high rate
(88Vo),predominantly in the olfactory bulbs, tracts, and
inferior frontal lobes. Qualitative and quantitative assess-
ments of damage show little correlation with olfactory
tests probably due to multifocal injury, ciliary nerve dam-
age, and the constraints of small sample size.
H. Brain Tirmors
The incidence of chemosensory changes caused by
intracranial tumors has rarely been investigated.In a study
of 750 consecutivepatients presenting with chemosensory
disorders to the University of Pennsylvania Smell and
Taste Center, only two cases (0.3%) were induced by
brain tumors (Deems et al., 1991). In one study anosmia
was reportedly present in 19 of the 26 cases of Foster-
Kennedy syndrome (retrobulbar optic neuritis, central
scotoma, optic atrophy on the side of the lesion and con-
tralateral papilledema usually occurring in tumors of the
frontal lobe of the brain which press downward) (Jarus
and Feldon, 1982).Bakay (1984) emphasizedthat loss of
smell perception is one of the first signs of olfactory
meningiomas.
In general,tumors or other destructivelesions involving
the olfactory bulb, tract, or prefrontal lobe may cause
olfactory deficits. Temporal lobe tumors usually cause
olfactory hallucinations. It is estimatedthat approximately
20% of the tumors of the temporal lobe produce some form
of olfactory disturbance (Furstenberg et al., 1943). The
presence of olfactory deficits correlates more with the
location of tumors than the histology (Fig. 5).
I. AcquiredlmmunodeficiencySyndrome
Olfactory deficits of patients with human immunodefi-
ciency virus (HIV) infection have been reported (Brody
et al., 1991;Heald et al., 1998).Theseauthorssuggestthat
impaired olfaction might serve as a marker of early central
nervous system HIV involvement. The principal
histopathological abnormalities in the brain of acquired
immunodeficiency syndrome (AIDS) patients are in the
subcortical structures,predominantly in the central white
matter, deep gray structures including the basal ganglia,
the thalamus, and the brain stem (Petito et al., 1986; Price
et al., 1988).Everall et al., (1991) havefound that the neu-
ronal numerical density in the frontal cortex is signifi-
cantly lower in HIV patients than in controls-a loss of
about38Voof neuronsin the superior frontal gyrus in AIDS
patients. This may account for the olfactory deficits in
these patients.
606
Figure 5 Temporallobe massin a 62-year-oldwoman with
olfactoryhallucinations.(A) T2W MR scanrevealsa relatively
well-definedright temporallobe masswith mild masseffect.(B)
Contrast-enhanced T1W MR image showsperipheralenhance-
ment of the tumor with a satellitenodule laterally.Sulci are
effacedandthe temporalhorn is obliterated.
Neuroradiological study has found that patients with
HIV infection show widened cortical sulci, enlarged ven-
tricles, cerebral atrophy, and brain stem atrophy when
comparedwith controls(Brun et al., 1986;Elovaaraet al.,
1990;Post et al., 1988).Opportunisticinfectionsand CNS
lymphoma may be superimposal on these changes. The
pathogenesis of the olfactory deficits of AIDS patients
needs further investigating but most likely will relate to
diseasein the prefrontal lobe. In addition to CNS changes,
sinusitis in HlV-infected patients is common and severe.
Li et al.
Therefore, the possibility of peripheral cause of olfactory
deficits in AIDS patients also has to be taken into account
in cerlain cases.
J. Multiple Sclerosis
Multiple sclerosis (MS), a markedly debilitating
neurological disease,affects millions of Americans in the
prime of their lives. Though the influence of MS on the
sense of smell has long been controversial, recent MRI
studies (Doty et al., 1991, 1999) have demonstratedthat
the olfactory function in patients with MS is closely corre-
lated with the number of demyelinating plaques within
central olfactory processing areas of the brain, as deter-
mined by MRI (Fig. 6, 7). A strong negative relationship
(Spearmanr : -0.94) was found between scores on the
University of Pennsylvania Smell Identification Test
(UPSIT) and the number of plaques within the inferior
frontal and temporal lobe regions (Doty et al., 1997). A
close associationwas present, longitudinally, between the
remission and exacerbationof plaque numbers and UPSIT
scores,with lower UPSIT scoresocculring during periods
of exacerbation(Doty et al., 1999).
K. Other Central Causes
There are also reports of olfactory dysfunction in
hypochondriasis, amyotrophic lateral sclerosis, epilepsy,
and migraine (Doty et al., 1991b; Mott and Leopold,
1991).Although the pathogenesisof olfactory dysfunction
in these disorders is still unclear, it appearsthat a central
mechanism is involved, rather than a peripheral one.
VL OVERVIEWANDDISCUSSION
It is apparentfrom the studiesreviewed in this chapter and
the information presented elsewhere in this volume that
olfactory dysfunction can be due to numerous causes.
Once an olfactory disorder has been recognized, the most
important step in the diagnostic processis to determine the
site of the lesion, i.e., anatomical localization.
Unfortunately, cur:rentclinical olfactory testing is unable
to localize the site of morphological changes(Doty et al.,
1984). Modern medical imaging techniquescan be of great
value in the anatomical classification and localization of
the common causes of olfactory dysfunction (Li et al.,
1994). The most common source of olfactory dysfunction
is the peripheralpathway (Goodspeedet al., 1987; Mott
and Leopold. 1991).In the evaluationofperipheral causes,
the "sinus series"radiographsoffer limited information. At
present, high-resolution CT, especially coronal scans, is
Medical Imaging of Olfactory Deficits
Figure 6 A 55-year-oldMS patientwith no significantolfac-
tory dysfunction,as measuredby the UPSIT.Axial T2W MRI
scanshowsno obviousplaquesin theinferiorfrontalandtempo-
ral loberegions(A). Numerousplaqueswereidentifiedin supra-
regions( B).
periventricular
the study of choice to look at the bony sinonasalstructures
and the ostiomeatal complex. CT can also provide impor-
tant information as a road map, which may be neededfor
surgical treatment.
MRI possessesspecial ability in soft tissue discrimina-
tion and offers multiplanar capabiTities.In the evaluation
of the central causesof olfactory disturbances,MRI has a
paramount role. Neuroimaging studies of patients with
olfactory deficits related to neuropsychiatric problems
have revealed interesting findings and possibly clues for
understandingsome of the links between olfactory deficits
and pathophysiological changes of the brain. The neu-
roimaging findings of patients with AD, KP, or schizo-
phrenia share some similarities. Thus, almost all of the
607
Figure 7 Axial TzW MRI scansfrom a severelymicrsomic
(UPSIT: 20) 50-year-old manwith an 8-yearhistoryof MS. The
placeof sectionin (A) is 6 mm belowthatof (B). Notethepromi-
nent plaques(10 X 5 mm each)within the posteriorpart of the
white matterof the gyrus rectusof the L and R subfrontallobe
regions(arrowsI and2,respectively), andtherelativelyhighsignal
intensityplaquesin the subtemporalloberegions(arrows3 and4).
abnormalities of the brain parenchyma revealed by neu-
roimaging studies in patients with AD, KP, or schizophre-
nia involve central brain areas that contain netrons of
olfactory projections including areasof the prefrontal lobe,
temporal lobe, hippocampus,and thalamus.
Recent studies have provided a clear physiological
explanation for decreasedolfactory function in patients
with MS (Doty et al., 1997, 1998, 1999). Current studies
from our laboratory suggest that MS, with its relatively
discrete focal regions of demyelination lesion, may be of
value in studying brain regions involved in sensory per-
ception in addition to olfaction.
It is much more difficult to explain the olfactory dys-
function in PD patients,and presentlyimaging studieshave
been of little use in clarifying this matter. Loss of olfaction
in these patients may be related to factors with dopamine
608
and dopamine receptors, although, as noted earlier, no
return of function accompaniest--dopa treatment. In addi-
tion, pathological changesin the areasof putamen and cau-
date nuclei, which have fibers connected with limbic
systemand striatum, may contribute to the loss of the sense
of smell. In this hypothesis,the olfactory dysfunction in PD
patientsmight sharea similar etiology to patientswith HD.
In congenital disorders, such as Kallmann's syndrome,
the cause of anosmia can be seen on MRI studies as the
absenceof olfactory bulbs (Yousem et al., 1993,1996a).
Other congenital abnormalities, such as choanal atresia
and meningoencephaloceles,also can be detectedby imag-
ing studies (Klein et al., 1987; Moorman et al., 1984).
In the categoriesof headtrauma and brain tumors. imag-
ing studieshave shown strong links betweenolfactory dys-
function and the location of the damaged brain. The
histology of the tumor or traumaticinjury is lesscritical than
its location (Costanzoand Zasler, 1991; Jamrs and Feldon,
1982; Schellingeret al., 1983;Yousemet al., 1996b).
Hyposmia or anosmia induced by occupational or acci-
dental exposure to toxins, as well as that induced by
intranasaluse of drugs such as cocaine, has been tradition-
ally thought to be due to damage to the peripheral path-
ways. However, one study has suggestedthat olfactory
deficits caused by occupational exposure to toxins may
have both peripheral toxic and CNS effects (Schwartz
et al., 1989).Imaging studies haye shown CNS complica-
tions in cocaine abusers(Holman et al., 1991; Kalkow et
al., 1988;Pascual-Leone et al., 1991;Tumethet al., 1990),
and one report ofanosmia as a sequelaofhydrogen sulfide
(H2S) inhalation suggestedthe loss to be due to central
brain damage (Tvedt et al., 1991).
VII. SUMMARY
Medial imaging is an essential part of the evaluation of
patients with olfactory disorders. In the assessmentof the
peripheral causesof olfactory deficits, medical imaging stud-
ies, especially CT and/or MRI, can reveal anatomical infor-
mation and structural changes,suggestdifferential diagnosis,
and provide the road map that may be needed for surgical
intervention. On the other hand, in the evaluation of the cen-
tral causes,MRI, f[4RI, PET, or SPECT can provide infor-
mation elucidating the links between olfactory dysfunction
and the structural or functional changesin the livine brain.
ACKNOWLEDGMENTS
Supported,in part, by Grants ROl DC04278, ROI
4G11496,ROl DC 02974,and POI DC0016l (R. L.
Doty, PrincipalInvestigator).
Li et al.
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